Herpes simplex viruses (HSV) establish persistent infections where the viruses modulate host immune systems in a complex way. Although many factors are involved, emerging evidence indicates that the interaction of HSV and dendritic cells is a key step which dictates the outcome of viral infection and pathogenesis. As sentinels, dendritic cells bridges innate and adaptive immunity. It is well documented that upon infection immature dendritic cells take up viral antigens, undergo maturation. In this process, co-stimulatory molecules such as MHC class II, CD40, CD80, and CD86 are up-regulated. Additionally, mature dendritic cells release inflammatory cytokines such as IL-6, IL-12, TNF-?, and type I interferon. These cellular factors coordinate with dendritic cells to control viral infection. Nevertheless, HSV replication compromises dendritic cell functions. Currently, little is known about underlying mechanisms due to the complex nature of HSV life cycles. The objective of this research is to understand the viral mechanisms through which HSV ?134.5 modulate dendritic cell maturation and functions. It is believed that this viral factor perturbs one or more of cellular components of Toll-like related innate signaling pathways in dendritic cells and impairs subsequent T cell activation in HSV infection. As such, multi-faceted approaches will be taken to investigate the roles of viral and cellular elements. Systematic analysis will be carried out to define critical functional domains in the context of viral replication and the induction of co-stimulatory molecules and cytokines. Additionally, studies will be performed to examine components and the nature of HSV and dendritic cell interactions relevant to viral pathogenesis. Together, these studies will not only advance our understanding of the mechanisms of viral infection but also provide an insight into dendritic cell functions in viral infections. PUBLIC HEALTH RELEVANCE: Herpes simplex viruses are human pathogens that cause diseases such as genital herpes, keratitis, blindness, and encephalitis. Herpes simplex virus infection is also a risk factor in HIV transmission. This research is designed to investigate how herpes simplex viruses impair the functions of immune cells which restrict viral infections. The proposed research may facilitate the development of novel vaccines and antiviral therapeutics.